Compounds of formula I: 
are structurally novel anticonvulsants (Maryanoff, B. E., Costanzo, M. J., Nortey, S. O., Greco, M. N., Shank, R. P., Schupsky, J. J., Ortegon, M. E., and Vaught, J. L. J. Med. Chem. 1998, 41, 1315-1343), found to possess anticonvulsant activity in the traditional maximal electroshock seizure (MES) test in mice and rats (Shank, R. P. et al., Epilepsia 1994, 35, 450-460). These compounds, covered by U.S. Pat. Nos. 5,242,942 and 5,498,629, are structurally related to 2,3:4,5-bis-O-(1-methylethylidene)-xcex2-D-fructopyranose sulfamate, topiramate, which has been demonstrated in clinical trials of human epilepsy to be effective as adjunctive therapy or as monotherapy in treating simple and complex partial seizures and secondarily generalized seizures, and is currently marketed in the United States of America, as well as other countries worldwide.
Recent preclinical studies on compounds of formula I have revealed previously unrecognized pharmacological properties, suggesting that such compounds will be effective in treating certain other neurological disorders. One of these, in particular, is acute ischemia-induced neurodegeneration, such as that which occurs during and after stroke, head trauma, spinal injury, non-fatal cardiac arrest, or major surgical procedures.
Accordingly, it has been found that anticonvulsant compounds of the following formula I: 
wherein X is oxygen or methylene, and R1, R2, R3, R4, R5, and R6 are as defined hereinafter, are useful in treating acute ischemia-induced neurodegeneration, such as occurs during and after head trauma, stroke, spinal injury, non-fatal cardiac arrest, or major surgical procedures.
The sulfamates of the invention are of the following formula (I): 
wherein
X is methylene or oxygen;
R1 and R2 are the same or different and chosen from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, benzyl, allyl, or C1-C6 perfluoroalkylmethyl, or taken together as N2 to define an azide group;
R3 and R4 are the same or different and chosen from hydrogen or C1-C6 alkyl;
R5 and R6 may be the same or different and are selected from oxygen, a lone pair of electrons or NR7; wherein R7 is selected from hydrogen, C1-C6 alkyl, C1-C6 perfluoroalkyl, arenesulfonyl, C1-C6 alkoxycarbonyl or arenemethyloxycarbonyl.
As used herein alkyl, alkoxy and perfluoroalkyl include straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 2-methyl-3-butyl, 1-methylbutyl, 2-methylbutyl, neopentyl, n-hexyl, 1-methylpentyl, 3-methylpentyl and n-octyl. Perfluoroalkyl radicals are defined as the previously described straight or branched chain alkyl radicals in which all of the hydrogen atoms have been replaced with fluorine atoms, e.g. trifluoromethyl, pentafluoroethyl, heptafluoropropyl, etc. Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. Arenesulfonyl radicals include, for example, phenylsulfonyl, o-toluenesulfonyl, m-toluenesulfonyl, p-toluenesulfonyl (abbreviated as xe2x80x9cTsxe2x80x9d), 1-naphthalenesulfonyl, 2-naphthalenesulfonyl, and 5-dimethylamino-1-naphthalenesulfonyl.
The compounds of formula I include the various individual isomers as well as the racemates thereof, e.g., the various alpha and beta attachments, i.e., below and above the plane of the drawing, of R3, R4, R5 and R6 on the 6-membered ring. Preferably, the oxygens of the methylenedioxy group of formula I are attached on the same side of the 6-membered ring.
Cyclic sulfites are designated when either R5 is oxygen and R6 is a lone pair of electrons and vice versa. Cyclic sulfates are designated when R5 and R6 are both oxygen. Cyclic imidosulfites are designated R5 is NR7 and R6 is a lone pair of electrons and vice versa. Cyclic imidosulfates are designated when R5 is NR7 and R6 is oxygen and vice versa. Cyclic diimidosulfates are designated when R5 and R6 both equal NR7.
The system of stereodescription developed by Cahn, Ingold and Prelog and described in Angew. Chem. Int. Ed. Engl. 1966, 5, 385 is used herein to describe the absolute stereochemistry of stereogenic sulfur atoms. For example, the structure of (R)-2,3-O-(1-methylethylidene)-4,5-O-sulfinyl-xcex2-D-fructopyranose sulfamate is shown below: 
Compounds of formula (I) can exist in the xcex2-D-fructopyranose and the xcex2-L-fructopyranose absolute configurations. As used herein, the xcex2-D-fructopyranose absolute configuration is defined as: 
and the xcex2-L-fructopyranose absolute configuration is defined as: 
Compounds of formula (I) can also exist in the pseudo-xcex2-D-fructopyranose and the xcex2-L-fructopyranose absolute configurations. As used herein, the pseudo-xcex2-D-fructopyranose absolute configuration is defined as: 
and the pseudo-xcex2-L-fructopyranose absolute configuration is defined as: 
A particular group of compounds of formula I is that wherein X is oxygen or methylene; R1 and R2 are the same or different and selected from hydrogen, methyl, or ethyl, or different with one equal to hydrogen and the other selected from cyclopropyl or cyclobutyl; R3 and R4 are the same or different and selected from hydrogen, methyl, or ethyl; R5 and R6 are both oxygen, or one is oxygen and the other a lone pair of electrons.
Preferred compounds of formula (I) are those wherein the compounds are in the xcex2-D-fructopyranose absolute configuration wherein X is oxygen or methylene; R1 and R2 are as defined above; R3 and R4 are methyl; R5 and R6 are oxygen. Particularly preferred compounds of formula (I) are those in the xcex2-D-fructopyranose absolute configuration wherein; X is oxygen; R1 and R2 are the same or different and selected from hydrogen, methyl, or ethyl, or different with one equal to hydrogen and the other selected from cyclopropyl or cyclobutyl; R3 and R4 are the same or different and selected from hydrogen, methyl, or ethyl; R5 and R6 are both oxygen, or one is oxygen and the other a lone pair of electrons.
In addition, the compounds of this invention also include any pharmaceutically acceptable salts, for example: alkali metal salts, such as sodium and potassium; ammonium salts; monoalkylammonium salts; dialkylammonium salts; trialkylammonium salts; tetraalkylammonium salts; and tromethamine salts. Hydrates and other solvates of the compound of the formula (I) are included within the scope of this invention.
Examples of specific compounds of formula (I) are:
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-xcex2-D-fructopyranose sulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1and R2 are hydrogen, R3 and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-xcex2-L-fructopyranose sulfamate, i.e. where the compound is in the xcex2-L-fructopyranose absolute configuration, X is oxygen, R1 and R2 are hydrogen, R3 and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-xcex2-D-fructopyranose methylsulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 is hydrogen, R2 is methyl, R3 and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-xcex2-D-fructopyranose butylsulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 is hydrogen, R2 is n-butyl, R3 and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-xcex2-D-fructopyranose ethylsulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 is hydrogen, R2is ethyl, R3and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-xcex2-D-fructopyranose octylsulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 is hydrogen, R2 is n-octyl, R3 and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-xcex2-D-fructopyranose 2-propenylsulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 is hydrogen, R2 is allyl, R3 and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-xcex2-D-fructopyranose phenylmethylsulfamate; i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 is hydrogen, R2 is benzyl, R3 and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-xcex2-D-fructopyranose cyclopropylsulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 is hydrogen, R2 is cyclopropyl, R3 and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-xcex2-D-fructopyranose cyclobutylsulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 is hydrogen, R2 is cyclobutyl, R3 and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-xcex2-D-fructopyranose cyclooctylsulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 is hydrogen, R2 is cyclooctyl, R3 and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-xcex2-D-fructopyranose (2,2,2-trifluoroethyl)-sulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 is hydrogen, R2 is 2,2,2-trifluoroethyl, R3 and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-xcex2-D-fructopyranose dimethylsulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 and R2 are methyl, R3 and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-xcex2-D-fructopyranose diethylsulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 and R2 are ethyl, R3 and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-xcex2-D-fructopyranose azidosulfate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 and R2 are taken together with the nitrogen of formula (I) to represent an azido (N3) group, R3 and R4 are methyl, R5 and R6 are oxygen;
(S)-2,3-O-(1-methylethylidene)-4,5-O-sulfinyl-xcex2-D-fructopyranose sulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 and R2 are hydrogen, R3 and R4 are methyl, R5 is oxygen, R6 is a lone pair of electrons, and the absolute stereochemistry at the sulfite sulfur is (S);
(R)-2,3-O-(1-methylethylidene)-4,5-O-sulfinyl-xcex2-D-fructopyranose sulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 and R2 are hydrogen, R3 and R4 are methyl, R5 is a lone pair of electrons, R6 is oxygen, and the absolute stereochemistry at the sulfite sulfur is (R);
2,3-O-(1-ethylpropylidene)-4,5-O-sulfonyl-xcex2-D-fructopyranose sulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 and R2 are hydrogen, R3 and R4 are ethyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-[N-(4-methylbenzenesulfonyl) imidosulfinyl]-xcex2-D-fructopyranose sulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 and R2 are hydrogen, R3 and R4 are methyl, R5 is NR7, R6is a lone pair of electrons, and R7is p-toluenesulfonyl;
2,3-O-(1-methylethylidene)-4,5-O-[N-(4-methylbenzenesulfonyl) imidosulfonyl]-xcex2-D-fructopyranose sulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 and R2 are hydrogen, R3 and R4 are methyl, R5 is NR7, R6 is oxygen, and R7 is p-toluenesulfonyl;
2,3-O-(cyclohexylidene)-4,5-O-sulfonyl-xcex2-D-fructopyranose sulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 and R2 are hydrogen, R3 and R4 are taken together with carbon to which they are both bonded to represent a cyclohexane ring, R5 and R6 are oxygen;
(R)-4,5-O-[N-(1,1-dimethylethoxycarbonyl)imidosulfinyl]-2,3-O-(1-methylethylidene)-xcex2-D-fructopyranose sulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 and R2 are hydrogen, R3 and R4 are methyl, R5 is a lone pair of electrons, R6 is NR7, R7 is t-butoxycarbonyl, and the absolute stereochemistry at the imidosulfite sulfur is (R);
(S)-4,5-O-[N-(1,1-dimethylethoxycarbonyl)imidosulfinyl]-2,3-O-(1-methylethylidene)-xcex2-D-fructopyranose sulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is oxygen, R1 and R2 are hydrogen, R3 and R4 are methyl, R5 is NR7, R6 is a lone pair of electrons, R7 is t-butoxycarbonyl, and the absolute stereochemistry at the imidosulfite sulfur is (S);
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-pseudo-xcex2-D-fructopyranose sulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is methylene, R1 and R2 are hydrogen, R3 and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-pseudo-xcex2-L-fructopyranose sulfamate, i.e. where the compound is in the xcex2-L-fructopyranose absolute configuration, X is methylene, R1 and R2 are hydrogen, R3 and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-pseudo-xcex2-D-fructopyranose methylsulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is methylene, R1 is hydrogen, R2 is methyl, R3 and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-pseudo-xcex2-D-fructopyranose cyclopropyl-sulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is methylene, R1 is hydrogen, R2 is cyclopropyl, R3 and R4 are methyl, R5 and R6 are oxygen;
2,3-O-(1-methylethylidene)-4,5-O-sulfonyl-pseudo-xcex2-D-fructopyranose cyclobutyl-sulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is methylene, R1 is hydrogen, R2 is cyclobutyl, R3 and R4 are methyl, R5 and R6 are oxygen;
(S)-2,3-O-(1-methylethylidene)-4,5-O-sulfinyl-pseudo-xcex2-D-fructopyranose sulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is methylene, R1 and R2 are hydrogen, R3 and R4 are methyl, R5 is oxygen, R6 is a lone pair of electrons, and the absolute stereochemistry at the sulfite sulfur is (S);
(R)-2,3-O-(1-methylethylidene)-4,5-O-sulfinyl-pseudo-xcex2-D-fructopyranose sulfamate, i.e. where the compound is in the xcex2-D-fructopyranose absolute configuration, X is methylene, R1 and R2 are hydrogen, R3 and R4 are methyl, R5 is a lone pair of electrons, R6 is oxygen, and the absolute stereochemistry at the sulfite sulfur is (R);
and the pharmaceutically acceptable salts thereof.
The compounds of formula I can be made by one skilled in the art of synthetic organic chemistry by the processes disclosed in U.S. Pat. Nos. 4,513,006, 5,242,942, and 5,498,629, which are incorporated by reference herein. These procedures are also described in greater detail in Maryanoff, B. E., Costanzo, M. J., Nortey, S. O., Greco, M. N., Shank, R. P., Schupsky, J. J., Ortegon, M. E., and Vaught, J. L. J. Med. Chem. 1998, 41, 1315-1334) and McComsey, D. F., Maryanoff, B. E . J. Org. Chem. 1994, 59, 2652-2654. Some example syntheses that are described in these references are as follows:
(a) Reaction of an alcohol of the formula RCH2OH with a chlorosulfamate of the formula ClSO2NH2 or ClSO2NHR1 in the presence of a base such as potassium tert-butoxide or sodium hydride at a temperature of about xe2x88x9220xc2x0 to 25xc2x0 C. and in a solvent such as toluene, THF or dimethylformamide wherein R is a moiety of formula II, wherein X, R3, R4, R5, and R6 are as previously defined. 
(b) Reaction of an alcohol of the formula RCH2OH with sulfuryl chloride in the presence of a base such as triethylamine or pyridine at a temperature of about xe2x88x9240xc2x0 to 25xc2x0 C. in a solvent such as diethyl ether or methylene chloride to produce a chlorosulfate of the formula RCH2OSO2Cl.
The chlorosulfate of the formula RCH2OSO2Cl may then be reacted with an amine of the formula R1R2NH at a temperature of about 40xc2x0 to 25xc2x0 C. in a solvent such as methylene chloride or acetonitrile to produce a compound of formula I. The reaction conditions for (b) are also described by T. Tsuchiya et al. in Tetrahedron Lett 1978, 36, 3365-3368.
(c) Reaction of the chlorosulfate RCH2OSO2Cl with a metal azide such as sodium azide in a solvent such as methylene chloride or acetonitrile yields an azidosulfate of the formula RCH2OSO2N3 as described by M. Hedayatullah in Tetrahedron Lett. 1975, 2455-2458. The azidosulfate is then reduced to a compound of formula (I) wherein R1 is hydrogen by catalytic hydrogenation, e.g. with a noble metal and H2 or by heating with copper metal in a solvent such as methanol.
For treating acute ischemia-induced neurodegeneration caused by stroke, head trauma, spinal injury, non-fatal cardiac arrest, or any major surgical procedure a compound of formula I may be employed by administering a single iv dosage in the range of about 25 to 1600 mg within a period of several hours after the medical condition is identified, for an average adult human.
Male Long-Evans rats (250 g) were obtained from Charles River Laboratories, Portage, Mich. The neurologic function and seizure susceptibility of each animal was tested according to the methods described below. The rats were housed in the experimental laboratory for at least 24 h prior to study to avoid transit stress and to ensure a 24-h fasting period. Only rats with blood glucose levels of 100 mg/dL or less at the end of fasting were used in the experiments.
General anesthesia was induced with ketamine (100 mg/kg, ip) and maintained with small fractional supplements as needed. Tracheal intubation was performed using a custom-made fiberoptic rodent laryngoscope and a 14-gauge polyethylene catheter. Needle electrodes were inserted in the scalp and thorax to monitor the EEG and ECG, respectively, while blood pressure was measured via an indwelling femoral arterial cannula. Body and brain temperatures were monitored by thermistors placed in the rectum and temporalis muscle, respectively. Once the temporalis temperature was stabilized at 34.5xc2x10.5xc2x0 C. the ischemic insult was produced by hydraulic atraumatic chest compression (3-kg force) for 11.0 min. Cranial temperature was maintained during circulatory arrest with the aid of a heat lamp. Chest compression resulted in complete global ischemia due to cardiac electromechanical dissociation. The completeness of the ischemic insult was verified by the absence of an arterial pressure waveform and EEG electrical activities. After the period of compression, resuscitation was initiated by external cardiac massage and mechanically assisted ventilation with 95% oxygen. Rats in which spontaneous ECG activity did not return within 5 min were immediately sacrificed. Assisted ventilation was continued until persistent spontaneous ventilation occurred. Rats requiring assisted ventilation for more than 1 h were sacrificed. After spontaneous respiration was restored, the inspired oxygen concentration was reduced to 50% and the rats were extubated 30 min later.
Neurologic assessment was identical to that described for the use with this model by Wauquier et al. (Neuropharmacology 1989; 28(8):837-846). Assessments were made on the fifth day following the insult by a single experienced observer who was blinded to the nature of the experimental variable. The assessment provided a 50-point clinical scoring system (0=normal, i.e., no deficit) that characterized decrements in cranial and spinal reflexes, postural tone, placing reactions, gait and spontaneous locomotor behavior. In addition to the neurodeficit score, the angle of inclination at which the rat could no longer cling to the inclined plane was determined. Performance was quantified as percent of preinsult baseline.
Audiogenic convulsions were induced in previously insulted rats by vigorously shaking a small ring of common house keys at a distance of 0.5 m for a period of 1 min. Keys were used because they were much more effective than high intensity (90 dB) pure tone (10 to 20 kHz ) stimuli used in preliminary observations. In their simplest form, the audiogenic convulsions were characterized by wild running, with increasing severity, convulsions progressed to clonus and ultimately whole body tonic extension. The postictal period was characterized by profound behavioral depression. The 9-point scale, originally developed by Dailey and Jobe (Fed Proc. 1985; 44: 2640-2644) for scoring audiogenic convulsions in genetically epilepsy-prone rats, was used to measure seizure severity. On this scale, 0 was normal and 9 was the most severe form of convulsion.
Postischemic injury (pyknosis, crenation) in hippocampal CA1 pyramidal neurons was quantified on the fifth recovery day. Rats were sacrificed by an overdose of pentobarbital and the brains were perfusion-fixed with 10% buffered formalin. Slides containing successive 10-micron sections of the CA1 hippocampal region (3000 xcexcm posterior to bregma) were stained with cresyl violet. A pair of representative slides containing dorsal hippocampus was obtained from each animal. Photographs of a medium power field were used to count ischemic (darkly stained) pyramidal neurons. Ischemic cell counts were expressed as a percent of the total number of CA1 neurons per photograph.
In addition to these subjective assessments of reperfusion injury, objective electrophysiologic measures were performed on 6 rats to more clearly document the character of the ischemic damage. During brainstem auditory evoked potential (BSAEP) analysis, the acoustic stimuli were rarefaction clicks delivered at 2 Hz and an intensity of 80 dB through miniature ear pieces. Two thousand responses were averaged, using a Cadwell 7400 signal analyzer. The latency from the stimulus artifact to the fourth positive component (wave IV) was used as a measure of brainstem excitability.
Conditions for the production of middle latency auditory evoked potentials (MLAEP) were the same. Since the middle latency components of the auditory evoked potentials are thought to arise from the thalamocortical radiations, a latency increase in the stable P1wave was used as a measure of depressed cortical auditory function. Recordings of both types of auditory evoked potentials were made from animals anesthetized with ketamine 100 mg/kg ip.
Somatosensory evoked potential (SSEP) and EEG recordings were made from awake unmedicated animals that were gently restrained with a soft cloth towel. During SSEP analysis, the posterior tibial nerve was stimulated with needle electrodes using a 100 xcexcsec pulse of 20 mA and 250 repetitions. Latency increase of the early stable P1 component indicated delayed transmission through spinal cord/brain stem sensory pathways.
A Probit analysis of the dose-response relationships was performed to establish ED50 values and the 95% confidence limits.
Under the experimental conditions described for this study, RWJ-37947 significantly reduced the ischemia-induced neurological deficit and the detrimental effect on exploratory behavior (Table 1).
The compounds of formula I preferably are administered in the form of a pharmaceutical composition. To prepare the pharmaceutical compositions of this invention, one or more sulfamate compounds of formula I are intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral, subcutaneous, parenteral or by suppository. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as, for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. Suppositories may be prepared, in which case cocoa butter could be used as the carrier. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The term xe2x80x9cunit dosage formxe2x80x9d as used in the specification and claims herein refers to physically discrete units suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
The pharmaceutical compositions herein will contain, per unit dosage, e.g., tablet, capsule, powder, injection, teaspoonful, suppository and the like. The compositions will be administrated in amounts as previously described herein with regard to the active ingredient and to the condition being treated. The dosages, however, may be varied depending upon the requirement of the patient, the severity of the condition being treated, and the compound being employed. Determination of optimum dosages for a particular situation is within the skill of the art.